Optimizing and Individualizing the Pharmacological Treatment of First-episode Schizophrenic Patients

The study is performed in 20 different hospitals from 19 cities in China. Three sub-projects are included. About sub-project 1, we build a clinical database system and a biological sample bank for data and samples management, which is applicable in other hospitals in this project. 1800 first-episode schizophrenia patients will be recruited in 19 sites and randomized into 6 treatment groups (olanzapine, risperidone, aripiprazole, ziprasidone, amisulpride, haloperidol). Through 8-week treatment and follow-up, we collect multidimensional indexes from psychopathology, neuropsychology, brain imaging, physiology, biochemistry, and life stress data. The summarized data is analyzed to screen potential biomarkers or biomarker panel that may predict the antipsychotic response, and ultimately to establish a prediction model.Sub-project 2, as an extension of sub-project 1, includes verification of the prediction model established in sub-project 1 and optimization of the current therapy with add-on treatment. Firstly, the validation process of the prediction model undergoes with an independent patient cohort. Next, we apply the add-on treatment to the patients who don't have ideal response to antipsychotic treatment after 8-week treatment. According to the results above, we manage to construct an optimized and individualized therapy for schizophrenia.In the end,We tend to conduct a randomized double-blind controlled trial to assess the safety and efficacy of the combination strategy for antipsychotic-induced metabolism syndrome, which includes metformin and lifestyle intervention. In the meanwhile, for schizophrenia patients at high-risk of metabolic syndrome, we tend to establish a prevention strategy expected to reduce or delay the occurrence of metabolic syndrome, which includes low-dose metformin and lifestyle intervention. We hope to successfully construct a comprehensive intervention strategy on metabolic syndrome induced by antipsychotic medications.

Study Overview

• Status: Completed
• Conditions: Schizophrenia; Metabolic Syndrome
• Intervention / Treatment: Drug: antipsychotic medications; Drug: adjunctive group; Drug: metformin and lifestyle intervention

Detailed Description

For sub-project1 and 2:Inclusion criteria: Participants are ineligible to enter the trial under the following conditions: 1) Participants must be aged 18 to 65 years old who meet the criteria for schizophrenia diagnosed by Diagnostic and Statistical Manual of Mental Disorders-fifth edition (DSM-5) or International Classification of Diseases- tenth edition (ICD-10); 2) participants are in current episode of psychotic symptoms with a disease course less than 3 years and intermission less than 6 months; 3). there is at least 1 guardian to accompany patient within 1 year; 4). Participants and their guardians must sign an Informed Consent Form (ICF) indicating that they understand the purpose of and procedures required for the study and are willing to participate in the study.

Exclusion criteria (any potential paticipant who meets any of the following criteria will be excluded from participating in the study): 1). Participants with known or suspected clinically unstable systemic medical disorder; 2). participant has a current or prior DSM-5/ ICD-10 diagnosis of substance use disorder, intellectual disability, autism spectrum disorder, dementia or severe cognitive impairment; 3). planning to be pregnant, pregnancy or breast-feeding; 4). currently enrolled in another clinical trial.

For sub-project 3:The diagnostic criteria for Paticipants who develop metabolic syndrome: A. body mass index ≥ 25.0kg / m2; B. hyperglycemia: fasting blood glucose ≥ 110mg/dl (6.1mmol/l) and / or plasma glucose ≥ 140mg/dl(7.8mmol/l) after glucose load; and / or those who have been diagnosed with diabetes and received treatment; C. hypertension: systolic blood pressure (SBP) / diastolic blood pressure (DBP) ≥ 140/90mmHg, and / or those who have been diagnosed as hypertension and received treatment; D. dyslipidemia: at fasting state, total cholesterol (TG) ≥ 150 mg/dl (1.7mmol/l); and / or HDL-C: male < 35mg/dl (0.9mmol/l), female < 39mg/dl (1.0mmol/l) . The inclusive criteria for patients at high-risk of MetS: A. paticipants are taking antipsychotic drugs that significantly affect metabolisms, such as olanzapine, clozapine or risperidone; B. paticipants have family history of diabetes, hypertension and heart disease; C. the age of paticipants is over 40 years old; D. paticipants have no nonalcoholic fatty liver and gout; E. paticipants who have one or two components of metabolic syndrome but do not meet the diagnostic criteria.

For clinical and biological data collection, we collect blood samples and case information, which contains demographic data, medical history (including current medical history, past history, personal history and family history), medication regimen and results of follow-up evaluation. The biological samples are stored using unique code whose storage information can be linked to research case in the web server.

The Standard Operations Procedures (SOPs) are followed for data collection, storage, tracking, and utilization.

Professional technicians are employed for the establishment and subsequent maintenance of Internet platform, including web server and mobile terminal applications (APP). Ancillary researchers are involved for collection and timely upload of case information online. Principal investigators are responsible for auditing the data and quality control.

• Study Type: Observational
• Enrollment (Actual): 2000

Contacts and Locations

Study Locations

• China
  • Hunan
    • Changsha, Hunan, China, 410011
      • Mental Health Institute of 2nd Xiangya Hospital,CSU

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 17 years to 65 years (Child, Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

• Sampling Method: Probability Sample

Study Population

Meet the Diagnostic and Statistical Manual (DSM-V) diagnostic criteria for schizophrenia;Duration of illness less than 3 years with current symptoms exacerbation;Male and female with aged 17 to 65 years;

Description

Inclusion Criteria:

1. Meet the Diagnostic and Statistical Manual (DSM-V) diagnostic criteria for schizophrenia;
2. Duration of illness less than 3 years with current symptoms exacerbation;
3. Male and female with aged 17 to 65 years;
4. Signed the study consent for participation

Exclusion Criteria:

1. Having history of substance dependence or abuse or whose symptoms are caused by the other diagnosable mental disorders;
2. Having history of traumatic brain injury, seizures or other known neurological or organic diseases of the central nervous system;
3. Taking antidepressants, stimulants, mood stabilizer or accepts electricity shock treatment;
4. Having current suicidal or homicidal thoughts or any safety concern by research staff that cannot be manage in an inpatient setting;
5. The routine blood tests showing abnormal renal, liver function;
6. Pregnant or lactating women.
7. No administration of any antibiotics in a mouth

Study Plan

How is the study designed?

Design Details

• Observational Models: Cohort
• Time Perspectives: Prospective

Number of groups / cohorts

5

Cohorts and Interventions

Group / Cohort	Intervention / Treatment
treatment cohort; in sub-project 1, participants are randomized into olanzapine, risperidone, aripiprazole, amisulpride, ziprasidone, and haloperidol groups, we give them evaluation, and adjust dose of medication and deal with side effect if necessary.	Drug: antipsychotic medications; olanzapine, risperidone, aripiprazole, amisulpride, ziprasidone, and haloperidol groups
adjunctive group; Patients who do not have an ideal response to antipsychotics treatment (reduction rate of Positive and Negative Symptom Scale (PANSS) score less than 25%) in sub-project 2 are recruited in this trial. They are randomly assigned to antipsychotic plus placebo, antipsychotic plus sulforaphane(3 tables per day, consisting of 30 mg of SFN-glucosinolate per day), and antipsychotic plus minocycline(200mg per day) groups, and the antipsychotic drugs used at this stage are still consistent with the first trial of sub-project 2. At baseline, 4 weeks and 8 weeks after treatment, all participants receive evaluations.	Drug: adjunctive group; antipsychotic plus placebo, antipsychotic plus sulforaphane(3 tables per day, consisting of 30 mg of SFN-glucosinolate per day), and antipsychotic plus minocycline(200mg per day) groups.
metformin and lifestyle intervention for MetS; Participants who develop MetS at the last visit in sub-project 1 and sub-project 2 are recruited in this trial. Patients are randomized into low-dose metformin (1000 mg/d), high-dose metformin (1500 mg/d), low dose metformin plus lifestyle intervention group (1000 mg/d), high dose metformin plus lifestyle intervention (1500 mg/d), lifestyle intervention, and placebo groups. The timepoints of the visits are at baseline, the 4th week, the 8th week, and the 12th week.	Drug: metformin and lifestyle intervention; different dose metformin combines lifestyle intervention
metformin and lifestyle prevention for high risk of MetS; Participants who are at a high risk of MetS are recruited in this trial. Participants are randomized into low dose metformin (750 mg/d), high dose metformin (1000 mg/d), lifestyle intervention, and placebo groups. The timepoints of the visits are at baseline, the 4th week, the 8th week, and the 12th week.	Drug: metformin and lifestyle intervention; different dose metformin combines lifestyle intervention
validation cohort; in sub-project 2, there are1,800 first-episode schizophrenia patients recruited from 19 hospitals, and six groups as with sub-project 1. The assessments (timepoint and content) are conducted as in sub-project 1.	Drug: antipsychotic medications; olanzapine, risperidone, aripiprazole, amisulpride, ziprasidone, and haloperidol groups

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Positive And Negative Syndrome Scale (PANSS)	The change of Positive And Negative Syndrome Scale (PANSS) total, positive and negative symptoms before and after treatment at different follow up point.	8 weeks
Clinical Global Impressions(CGI)	The change of Clinical Global Impressions(CGI):severity of illness(SI), global improvement(GI) and efficacy index(EI) before and after treatment at different follow up point.	8 weeks
Global Assessment Function(GAF)	The change of Global Assessment Function(GAF) before and after treatment at different follow up point.	8 weeks
MATRICS Consensus Cognitive Battery (MCCB) composite score	The investigators will use the MATRICS Consensus Cognitive Battery (MCCB) Composite score as primary cognitive outcome measure before and after treatment at different follow up point.	8 weeks

Collaborators and Investigators

• Sponsor: Central South University
• Collaborators: China Medical University, China; Xiangya Hospital of Central South University; Sun Yat-sen University; Shanghai Mental Health Center; West China Hospital; First Affiliated Hospital Xi'an Jiaotong University; First Affiliated Hospital of Zhejiang University; The First Affiliated Hospital of Zhengzhou University; Shanghai Jiao Tong University School of Medicine; Air Force Military Medical University, China; Wuhan Mental Health Centre; The First Affiliated Hospital of Kunming Medical College; Capital Medical University; First Affiliated Hospital of Chongqing Medical University; First Affiliated Hospital of Harbin Medical University; Hebei Medical University; Shanxi Medical University; Shenzhen Mental Health Center; Guangzhou Mental Hospital; Jiangsu Province Nanjing Brain Hospital

Publications and helpful links

General Publications

• Xiao J, Huang J, Long Y, Wang X, Wang Y, Yang Y, Hei G, Sun M, Zhao J, Li L, Shao T, Wang W, Kang D, Liu C, Xie P, Huang Y, Wu R, Zhao J. Optimizing and Individualizing the Pharmacological Treatment of First-Episode Schizophrenic Patients: Study Protocol for a Multicenter Clinical Trial. Front Psychiatry. 2021 Feb 25;12:611070. doi: 10.3389/fpsyt.2021.611070. eCollection 2021.
• Peng XJ, Hei GR, Li RR, Yang Y, Liu CC, Xiao JM, Long YJ, Shao P, Huang J, Zhao JP, Wu RR. The Association Between Metabolic Disturbance and Cognitive Impairments in Early-Stage Schizophrenia. Front Hum Neurosci. 2021 Feb 22;14:599720. doi: 10.3389/fnhum.2020.599720. eCollection 2020. Erratum In: Front Hum Neurosci. 2022 Nov 21;16:1094810.
• Huang J, Hei GR, Yang Y, Liu CC, Xiao JM, Long YJ, Peng XJ, Yang Y, Zhao JP, Wu RR. Increased Appetite Plays a Key Role in Olanzapine-Induced Weight Gain in First-Episode Schizophrenia Patients. Front Pharmacol. 2020 May 22;11:739. doi: 10.3389/fphar.2020.00739. eCollection 2020. Erratum In: Front Pharmacol. 2020 Jun 10;11:878.

Study record dates

Study Major Dates

• Study Start (Actual): January 23, 2018
• Primary Completion (Actual): June 30, 2021
• Study Completion (Actual): June 30, 2021

Study Registration Dates

• First Submitted: January 23, 2018
• First Submitted That Met QC Criteria: February 24, 2018
• First Posted (Actual): March 2, 2018

Study Record Updates

• Last Update Posted (Actual): August 12, 2021
• Last Update Submitted That Met QC Criteria: August 10, 2021
• Last Verified: August 1, 2021

More Information

Terms related to this study

• Keywords: Biomarker; Efficacy; Side Effect; Optimized and individualized antipsychotic treatment
• Additional Relevant MeSH Terms: Mental Disorders; Glucose Metabolism Disorders; Metabolic Diseases; Schizophrenia Spectrum and Other Psychotic Disorders; Insulin Resistance; Hyperinsulinism; Schizophrenia; Metabolic Syndrome; Hypoglycemic Agents; Physiological Effects of Drugs; Central Nervous System Depressants; Tranquilizing Agents; Psychotropic Drugs; Metformin; Antipsychotic Agents
• Other Study ID Numbers: 2016YFC1306900

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No